Abstract

Iron overload results in cellular toxicity, tissue injury, organ fibrosis and increased risk of neoplastic transformation. SerpinB3 is a serine protease inhibitor overexpressed in the liver in oxidative stress conditions, able to induce fibrosis and increased risk of malignant transformation. Aim of the present study was to assess the effect of iron overload on SerpinB3 expression in the liver using in vivo and in vitro models.

The expression of Serpinb3 was assessed in the liver of hemojuvelin knockout mice (Hjv−/−), an established model of hereditary hemochromatosis, and of wild type control mice, following dietary or pharmacological iron manipulation. To assess the direct effect of iron in vitro, cell lines were treated with different concentration of hemin or with an iron chelator.

Hepatic Serpinb3 mRNA and protein were highly expressed in Hjv−/− mice, but not in wild type controls fed with a standard diet. Serpinb3 became detectable in wild type mice fed with a high iron diet or injected with iron dextran; these treatments further induced Serpinb3 expression in Hjv−/− mice. Livers expressing Serpinb3 showed a positive staining also for HIF-2α in the same areas. Hemin promoted induction of SerpinB3 mRNA in HeLa and HA22T/VGH cells, but a mild stimulation of SerpinB3 promoter activity in HeLa and Huh7 cells. In conclusion, Serpinb3 is strongly induced by iron in the mouse liver. The molecular link between iron, ROS and SerpinB3 seems to be HIF-2α, which is induced by iron overload and was previously found capable of up-regulating SerpinB3 at the transcriptional level.

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Footnotes

Contributors CT, PK, PP, GS, and KP conceived and designed the experiments; CT, PK, SC and EM performed the experiments; CT, LT, AB, and DS analyzed the data; CT wrote the paper; PP, MP, and KP revised the paper. All Authors had final approval of the submitted manuscript.

Funding This work obtained financial support by the Associazione Italiana per la Ricerca sul Cancro and the Canadian Institutes for Health Research.

Correction notice This article has been corrected since it was published Online First. The affiliation for the first author has been updated to Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy.

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